A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity

Vincent Lombardi, Philippe Stock, Abinav K. Singh, Jerome Kerzerho, Wen Yang, Barbara A. Sullivan, Xiangming Li, Takayuki Shiratsuchi, Nathan E. Hnatiuk, Amy R. Howell, Karl O A Yu, Steven A. Porcelli, Moriya Tsuji, Mitchell Kronenberg, S. Brian Wilson, Omid Akbari

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyper-reactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of a-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

Original languageEnglish (US)
Pages (from-to)2107-2115
Number of pages9
JournalJournal of Immunology
Volume184
Issue number4
DOIs
StatePublished - Feb 15 2010

Fingerprint

Natural Killer T-Cells
Allergens
Asthma
Galactosylceramides
Cell- and Tissue-Based Therapy
phosphatidylethanolamine
Protein-Tyrosine Kinases
Animal Models
Phosphorylation
Lymphocytes
Lipids
Lung
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity. / Lombardi, Vincent; Stock, Philippe; Singh, Abinav K.; Kerzerho, Jerome; Yang, Wen; Sullivan, Barbara A.; Li, Xiangming; Shiratsuchi, Takayuki; Hnatiuk, Nathan E.; Howell, Amy R.; Yu, Karl O A; Porcelli, Steven A.; Tsuji, Moriya; Kronenberg, Mitchell; Wilson, S. Brian; Akbari, Omid.

In: Journal of Immunology, Vol. 184, No. 4, 15.02.2010, p. 2107-2115.

Research output: Contribution to journalArticle

Lombardi, V, Stock, P, Singh, AK, Kerzerho, J, Yang, W, Sullivan, BA, Li, X, Shiratsuchi, T, Hnatiuk, NE, Howell, AR, Yu, KOA, Porcelli, SA, Tsuji, M, Kronenberg, M, Wilson, SB & Akbari, O 2010, 'A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity', Journal of Immunology, vol. 184, no. 4, pp. 2107-2115. https://doi.org/10.4049/jimmunol.0901208
Lombardi, Vincent ; Stock, Philippe ; Singh, Abinav K. ; Kerzerho, Jerome ; Yang, Wen ; Sullivan, Barbara A. ; Li, Xiangming ; Shiratsuchi, Takayuki ; Hnatiuk, Nathan E. ; Howell, Amy R. ; Yu, Karl O A ; Porcelli, Steven A. ; Tsuji, Moriya ; Kronenberg, Mitchell ; Wilson, S. Brian ; Akbari, Omid. / A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity. In: Journal of Immunology. 2010 ; Vol. 184, No. 4. pp. 2107-2115.
@article{78ccd5a33b2442b29cf8cb996e077ef6,
title = "A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity",
abstract = "The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyper-reactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of a-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.",
author = "Vincent Lombardi and Philippe Stock and Singh, {Abinav K.} and Jerome Kerzerho and Wen Yang and Sullivan, {Barbara A.} and Xiangming Li and Takayuki Shiratsuchi and Hnatiuk, {Nathan E.} and Howell, {Amy R.} and Yu, {Karl O A} and Porcelli, {Steven A.} and Moriya Tsuji and Mitchell Kronenberg and Wilson, {S. Brian} and Omid Akbari",
year = "2010",
month = "2",
day = "15",
doi = "10.4049/jimmunol.0901208",
language = "English (US)",
volume = "184",
pages = "2107--2115",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "4",

}

TY - JOUR

T1 - A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity

AU - Lombardi, Vincent

AU - Stock, Philippe

AU - Singh, Abinav K.

AU - Kerzerho, Jerome

AU - Yang, Wen

AU - Sullivan, Barbara A.

AU - Li, Xiangming

AU - Shiratsuchi, Takayuki

AU - Hnatiuk, Nathan E.

AU - Howell, Amy R.

AU - Yu, Karl O A

AU - Porcelli, Steven A.

AU - Tsuji, Moriya

AU - Kronenberg, Mitchell

AU - Wilson, S. Brian

AU - Akbari, Omid

PY - 2010/2/15

Y1 - 2010/2/15

N2 - The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyper-reactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of a-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

AB - The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyper-reactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of a-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

UR - http://www.scopus.com/inward/record.url?scp=77949899445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949899445&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0901208

DO - 10.4049/jimmunol.0901208

M3 - Article

C2 - 20083656

AN - SCOPUS:77949899445

VL - 184

SP - 2107

EP - 2115

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -